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1.
J Lipid Res ; : 100621, 2024 Aug 14.
Article in English | MEDLINE | ID: mdl-39151590

ABSTRACT

The rapid increase in lipidomic studies has led to a collaborative effort within the community to establish standards and criteria for producing, documenting, and disseminating data. Creating a dynamic easy-to-use checklist that condenses key information about lipidomic experiments into common terminology will enhance the field's consistency, comparability, and repeatability. Here, we describe the structure and rationale of the established Lipidomics Minimal Reporting Checklist to increase transparency in lipidomics research.

2.
Sci Rep ; 14(1): 17423, 2024 07 29.
Article in English | MEDLINE | ID: mdl-39075118

ABSTRACT

Inflammation is an important factor in Alzheimer's disease (AD). An NMR measurement in plasma, glycoprotein acetyls (GlycA), captures the overall level of protein production and glycosylation implicated in systemic inflammation. With its additional advantage of reducing biological variability, GlycA might be useful in monitoring the relationship between peripheral inflammation and brain changes relevant to AD. However, the associations between GlycA and these brain changes have not been fully evaluated. Here, we performed Spearman's correlation analyses to evaluate these associations cross-sectionally and determined whether GlycA can inform AD-relevant longitudinal measurements among participants in the Alzheimer's Disease Neuroimaging Initiative (n = 1506), with additional linear models and stratification analyses to evaluate the influences of sex or diagnosis status and confirm findings from Spearman's correlation analyses. We found that GlycA was elevated in AD patients compared to cognitively normal participants. GlycA correlated negatively with multiple concurrent regional brain volumes in females diagnosed with late mild cognitive impairment (LMCI) or AD. Baseline GlycA level was associated with executive function decline at 3-9 year follow-up in participants diagnosed with LMCI at baseline, with similar but not identical trends observed in the future decline of memory and entorhinal cortex volume. Results here indicated that GlycA is an inflammatory biomarker relevant to AD pathogenesis and that the stage of LMCI might be relevant to inflammation-related intervention.


Subject(s)
Alzheimer Disease , Atrophy , Brain , Cognitive Dysfunction , Inflammation , Humans , Alzheimer Disease/pathology , Female , Cognitive Dysfunction/pathology , Male , Aged , Brain/pathology , Brain/diagnostic imaging , Inflammation/pathology , Aged, 80 and over , Cross-Sectional Studies , Biomarkers/blood , Magnetic Resonance Imaging , Glycoproteins/blood , Glycoproteins/metabolism
3.
NPJ Metab Health Dis ; 2(1): 15, 2024.
Article in English | MEDLINE | ID: mdl-38962750

ABSTRACT

Alzheimer's disease (AD) is influenced by a variety of modifiable risk factors, including a person's dietary habits. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored KD's metabolic impact, especially on blood and cerebrospinal fluid (CSF). Our study involved participants at risk for AD, either cognitively normal or with mild cognitive impairment. The participants consumed both a modified Mediterranean Ketogenic Diet (MMKD) and the American Heart Association diet (AHAD) for 6 weeks each, separated by a 6-week washout period. We employed nuclear magnetic resonance (NMR)-based metabolomics to profile serum and CSF and metagenomics profiling on fecal samples. While the AHAD induced no notable metabolic changes, MMKD led to significant alterations in both serum and CSF. These changes included improved modifiable risk factors, like increased HDL-C and reduced BMI, reversed serum metabolic disturbances linked to AD such as a microbiome-mediated increase in valine levels, and a reduction in systemic inflammation. Additionally, the MMKD was linked to increased amino acid levels in the CSF, a breakdown of branched-chain amino acids (BCAAs), and decreased valine levels. Importantly, we observed a strong correlation between metabolic changes in the CSF and serum, suggesting a systemic regulation of metabolism. Our findings highlight that MMKD can improve AD-related risk factors, reverse some metabolic disturbances associated with AD, and align metabolic changes across the blood-CSF barrier.

4.
JCO Precis Oncol ; 8: e2400260, 2024 Jul.
Article in English | MEDLINE | ID: mdl-39074346

ABSTRACT

PURPOSE: Intense androgen deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPIs) before radical prostatectomy (RP) produced favorable pathologic responses in approximately 20% of patients. The molecular reason for the low rate of response remains unclear. Lipid metabolism is known to influence androgen receptor signaling and ARPI efficacy. The aim of the study was to identify circulating lipid profiles associated with ADT/ARPI resistance in localized prostate cancer. MATERIALS AND METHODS: Two independent experimental approaches were used. Experiment 1: Post hoc analysis of the association between plasma lipidomic profiles and ADT/ARPI response was performed on patients (n = 104) from two phase II trials of neoadjuvant ADT/ARPI. Response to ADT/ARPI was defined by pathologic response. Experiment 2: Patient-derived tumor explants from RP (n = 105) were cultured in enzalutamide for 48 hours. Explant response to enzalutamide was evaluated against pre-RP plasma lipidomic profiles (n = 105) and prostate tissue lipidomic profiles (n = 36). Response was defined by Ki67 (cell proliferation marker) fold difference between enzalutamide and vehicle-treated explants. In both experiments, associations between lipid profiles and ADT/ARPI response were analyzed by latent class analysis. RESULTS: Pretreatment plasma lipid profiles classified each experimental cohort into two groups with differences in ADT/ARPI response rates. The response rates of the groups were 9.6% versus 29% in experiment 1 (chi-squared test P = .012) and 49% versus 70% in experiment 2 (chi-squared test P = .037). In both experiments, the group with a higher incidence of ADT/ARPI resistance had higher plasma levels of sphingomyelin, glycosylceramides, free fatty acids, acylcarnitines, cholesterol esters, and alkyl/alkenyl-phosphatidylcholine and lower plasma levels of triacylglycerols, diacylglycerols, and phosphoethanolamine (t-test P < .05). CONCLUSION: Pretreatment circulating lipid profiles are associated with ADT/ARPI resistance in localized cancer in both human cohorts and explant models.


Subject(s)
Androgen Antagonists , Prostatic Neoplasms , Humans , Male , Androgen Antagonists/therapeutic use , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/blood , Prostatic Neoplasms/pathology , Prostatic Neoplasms/surgery , Drug Resistance, Neoplasm , Aged , Lipids/blood , Middle Aged , Lipidomics , Nitriles/therapeutic use , Prostatectomy
5.
J Am Coll Cardiol ; 84(5): 434-446, 2024 Jul 30.
Article in English | MEDLINE | ID: mdl-39048275

ABSTRACT

BACKGROUND: Accurate risk stratification is vital for primary prevention of cardiovascular disease (CVD). However, traditional tools such as the Framingham Risk Score (FRS) may underperform within the diverse intermediate-risk group, which includes individuals requiring distinct management strategies. OBJECTIVES: This study aimed to develop a lipidomic-enhanced risk score (LRS), specifically targeting risk prediction and reclassification within the intermediate group, benchmarked against the FRS. METHODS: The LRS was developed via a machine learning workflow using ridge regression on the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab; n = 10,339). It was externally validated with the Busselton Health Study (n = 4,492), and its predictive utility for coronary artery calcium scoring (CACS)-based outcomes was independently validated in the BioHEART cohort (n = 994). RESULTS: LRS significantly improved discrimination metrics for the intermediate-risk group in both AusDiab and Busselton Health Study cohorts (all P < 0.001), increasing the area under the curve for CVD events by 0.114 (95% CI: 0.1123-0.1157) and 0.077 (95% CI: 0.0755-0.0785), with a net reclassification improvement of 0.36 (95% CI: 0.21-0.51) and 0.33 (95% CI: 0.15-0.49), respectively. For CACS-based outcomes in BioHEART, LRS achieved a significant area under the curve improvement of 0.02 over the FRS (0.76 vs 0.74; P < 1.0 × 10-5). A simplified, clinically applicable version of LRS was also created that had comparable performance to the original LRS. CONCLUSIONS: LRS, augmenting the FRS, presents potential to improve intermediate-risk stratification and to predict atherosclerotic markers using a simple blood test, suitable for clinical application. This could facilitate the triage of individuals for noninvasive imaging such as CACS, fostering precision medicine in CVD prevention and management.


Subject(s)
Cardiovascular Diseases , Primary Prevention , Humans , Primary Prevention/methods , Risk Assessment/methods , Female , Cardiovascular Diseases/prevention & control , Middle Aged , Male , Lipidomics/methods , Aged , Heart Disease Risk Factors , Australia/epidemiology , Machine Learning , Adult
6.
Am J Prev Cardiol ; 18: 100672, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38828126

ABSTRACT

Background: Primary prevention programs utilising traditional risk scores fail to identify all individuals who suffer acute cardiovascular events. We aimed to model the impact and cost effectiveness of incorporating a Polygenic risk scores (PRS) into the cardiovascular disease CVD primary prevention program in Australia, using a whole-of-system model. Methods: System dynamics models, encompassing acute and chronic CVD care in the Australian healthcare setting, assessing the cost-effectiveness of incorporating a CAD-PRS in the primary prevention setting. The time horizon was 10-years. Results: Pragmatically incorporating a CAD-PRS in the Australian primary prevention setting in middle-aged individuals already attending a Heart Health Check (HHC) who are determined to be at low or moderate risk based on the 5-year Framingham risk score (FRS), with conservative assumptions regarding uptake of PRS, could have prevented 2, 052 deaths over 10-years, and resulted in 24, 085 QALYs gained at a cost of $19, 945 per QALY with a net benefit of $724 million. If all Australians overs the age of 35 years old had their FRS and PRS performed, and acted upon, 12, 374 deaths and 60, 284 acute coronary events would be prevented, with 183, 682 QALYs gained at a cost of $18, 531 per QALY, with a net benefit of $5, 780 million. Conclusions: Incorporating a CAD-PRS in a contemporary primary prevention setting in Australia would result in substantial health and societal benefits and is cost-effective. The broader the uptake of CAD-PRS in the primary prevention setting in middle-aged Australians, the greater the impact and the more cost-effective the strategy.

7.
EBioMedicine ; 105: 105187, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38861870

ABSTRACT

BACKGROUND: Decreased levels of circulating ethanolamine plasmalogens [PE(P)], and a concurrent increase in phosphatidylethanolamine (PE) are consistently reported in various cardiometabolic conditions. Here we devised, a plasmalogen score (Pls Score) that mirrors a metabolic signal that encompasses the levels of PE(P) and PE and captures the natural variation in circulating plasmalogens and perturbations in their metabolism associated with disease, diet, and lifestyle. METHODS: We utilised, plasma lipidomes from the Australian Obesity, Diabetes and Lifestyle study (AusDiab; n = 10,339, 55% women) a nationwide cohort, to devise the Pls Score and validated this in the Busselton Health Study (BHS; n = 4,492, 56% women, serum lipidome) and in a placebo-controlled crossover trial involving Shark Liver Oil (SLO) supplementation (n = 10, 100% men). We examined the association of the Pls Score with cardiometabolic risk factors, type 2 diabetes mellitus (T2DM), cardiovascular disease and all-cause mortality (over 17 years). FINDINGS: In a model, adjusted for age, sex and BMI, individuals in the top quintile of the Pls Score (Q5) relative to Q1 had an OR of 0.31 (95% CI 0.21-0.43), 0.39 (95% CI 0.25-0.61) and 0.42 (95% CI 0.30-0.57) for prevalent T2DM, incident T2DM and prevalent cardiovascular disease respectively, and a 34% lower mortality risk (HR = 0.66; 95% CI 0.56-0.78). Significant associations between diet and lifestyle habits and Pls Score exist and these were validated through dietary supplementation of SLO that resulted in a marked change in the Pls Score. INTERPRETATION: The Pls Score as a measure that captures the natural variation in circulating plasmalogens, was not only inversely related to cardiometabolic risk and all-cause mortality but also associate with diet and lifestyle. Our results support the potential utility of the Pls Score as a biomarker for metabolic health and its responsiveness to dietary interventions. Further research is warranted to explore the underlying mechanisms and optimise the practical implementation of the Pls Score in clinical and population settings. FUNDING: National Health and Medical Research Council (NHMRC grant 233200), National Health and Medical Research Council of Australia (Project grant APP1101320), Health Promotion Foundation of Western Australia, and National Health and Medical Research Council of Australia Senior Research Fellowship (#1042095).


Subject(s)
Biomarkers , Plasmalogens , Humans , Plasmalogens/blood , Plasmalogens/metabolism , Female , Male , Middle Aged , Diabetes Mellitus, Type 2/metabolism , Australia/epidemiology , Cross-Over Studies , Adult , Cardiovascular Diseases/mortality , Cardiovascular Diseases/prevention & control , Aged , Phosphatidylethanolamines/metabolism , Life Style , Cardiometabolic Risk Factors
8.
EBioMedicine ; 105: 105199, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38905750

ABSTRACT

BACKGROUND: Metabolic ageing biomarkers may capture the age-related shifts in metabolism, offering a precise representation of an individual's overall metabolic health. METHODS: Utilising comprehensive lipidomic datasets from two large independent population cohorts in Australia (n = 14,833, including 6630 males, 8203 females), we employed different machine learning models, to predict age, and calculated metabolic age scores (mAge). Furthermore, we defined the difference between mAge and age, termed mAgeΔ, which allow us to identify individuals sharing similar age but differing in their metabolic health status. FINDINGS: Upon stratification of the population into quintiles by mAgeΔ, we observed that participants in the top quintile group (Q5) were more likely to have cardiovascular disease (OR = 2.13, 95% CI = 1.62-2.83), had a 2.01-fold increased risk of 12-year incident cardiovascular events (HR = 2.01, 95% CI = 1.45-2.57), and a 1.56-fold increased risk of 17-year all-cause mortality (HR = 1.56, 95% CI = 1.34-1.79), relative to the individuals in the bottom quintile group (Q1). Survival analysis further revealed that men in the Q5 group faced the challenge of reaching a median survival rate due to cardiovascular events more than six years earlier and reaching a median survival rate due to all-cause mortality more than four years earlier than men in the Q1 group. INTERPRETATION: Our findings demonstrate that the mAge score captures age-related metabolic changes, predicts health outcomes, and has the potential to identify individuals at increased risk of metabolic diseases. FUNDING: The specific funding of this article is provided in the acknowledgements section.


Subject(s)
Biomarkers , Cardiometabolic Risk Factors , Cardiovascular Diseases , Lipidomics , Humans , Male , Female , Middle Aged , Lipidomics/methods , Aged , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/etiology , Cardiovascular Diseases/mortality , Adult , Aging/metabolism , Australia/epidemiology , Age Factors , Risk Factors , Risk Assessment/methods
9.
JCO Precis Oncol ; 8: e2300690, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38691814

ABSTRACT

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of cytotoxic cancer treatment, often necessitating dose reduction (DR) or chemotherapy discontinuation (CD). Studies on peripheral neuropathy related to chemotherapy, obesity, and diabetes have implicated lipid metabolism. This study examined the association between circulating lipids and CIPN. METHODS: Lipidomic analysis was performed on plasma samples from 137 patients receiving taxane-based treatment. CIPN was graded using Total Neuropathy Score-clinical version (TNSc) and patient-reported outcome measure European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN (EORTC-QLQ-CIPN20). RESULTS: A significant proportion of elevated baseline lipids were associated with high-grade CIPN defined by TNSc and EORTC-QLQ-CIPN20 including triacylglycerols (TGs). Multivariable Cox regression on lipid species, adjusting for BMI, age, and diabetes, showed several elevated baseline TG associated with shorter time to DR/CD. Latent class analysis identified two baseline lipid profiles with differences in risk of CIPN (hazard ratio, 2.80 [95% CI, 1.50 to 5.23]; P = .0013). The higher risk lipid profile had several elevated TG species and was independently associated with DR/CD when modeled with other clinical factors (diabetes, age, BMI, or prior numbness/tingling). CONCLUSION: Elevated baseline plasma TG is associated with an increased risk of CIPN development and warrants further validation in other cohorts. Ultimately, this may enable therapeutic intervention.


Subject(s)
Bridged-Ring Compounds , Lipidomics , Peripheral Nervous System Diseases , Triglycerides , Humans , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/blood , Female , Male , Middle Aged , Triglycerides/blood , Risk Factors , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Adult , Taxoids/adverse effects , Taxoids/therapeutic use
10.
Dev Cell ; 59(15): 1988-2004.e11, 2024 Aug 05.
Article in English | MEDLINE | ID: mdl-38781975

ABSTRACT

The transcription factor EHF is highly expressed in the lactating mammary gland, but its role in mammary development and tumorigenesis is not fully understood. Utilizing a mouse model of Ehf deletion, herein, we demonstrate that loss of Ehf impairs mammary lobuloalveolar differentiation at late pregnancy, indicated by significantly reduced levels of milk genes and milk lipids, fewer differentiated alveolar cells, and an accumulation of alveolar progenitor cells. Further, deletion of Ehf increased proliferative capacity and attenuated prolactin-induced alveolar differentiation in mammary organoids. Ehf deletion also increased tumor incidence in the MMTV-PyMT mammary tumor model and increased the proliferative capacity of mammary tumor organoids, while low EHF expression was associated with higher tumor grade and poorer outcome in luminal A and basal human breast cancers. Collectively, these findings establish EHF as a non-redundant regulator of mammary alveolar differentiation and a putative suppressor of mammary tumorigenesis.


Subject(s)
Breast Neoplasms , Cell Differentiation , Mammary Glands, Animal , Animals , Female , Mice , Mammary Glands, Animal/pathology , Mammary Glands, Animal/metabolism , Mammary Glands, Animal/growth & development , Mammary Glands, Animal/cytology , Breast Neoplasms/pathology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Humans , Carcinogenesis/pathology , Carcinogenesis/metabolism , Carcinogenesis/genetics , Cell Lineage , Transcription Factors/metabolism , Transcription Factors/genetics , Cell Proliferation , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/cytology , Pregnancy , Lactation
11.
Nat Cell Biol ; 26(4): 645-659, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38589531

ABSTRACT

The cellular lipidome comprises thousands of unique lipid species. Here, using mass spectrometry-based targeted lipidomics, we characterize the lipid landscape of human and mouse immune cells ( www.cellularlipidatlas.com ). Using this resource, we show that immune cells have unique lipidomic signatures and that processes such as activation, maturation and development impact immune cell lipid composition. To demonstrate the potential of this resource to provide insights into immune cell biology, we determine how a cell-specific lipid trait-differences in the abundance of polyunsaturated fatty acid-containing glycerophospholipids (PUFA-PLs)-influences immune cell biology. First, we show that differences in PUFA-PL content underpin the differential susceptibility of immune cells to ferroptosis. Second, we show that low PUFA-PL content promotes resistance to ferroptosis in activated neutrophils. In summary, we show that the lipid landscape is a defining feature of immune cell identity and that cell-specific lipid phenotypes underpin aspects of immune cell physiology.


Subject(s)
Ferroptosis , Humans , Animals , Mice , Fatty Acids, Unsaturated
12.
Nat Commun ; 15(1): 1540, 2024 Feb 20.
Article in English | MEDLINE | ID: mdl-38378775

ABSTRACT

Recent advancements in plasma lipidomic profiling methodology have significantly increased specificity and accuracy of lipid measurements. This evolution, driven by improved chromatographic and mass spectrometric resolution of newer platforms, has made it challenging to align datasets created at different times, or on different platforms. Here we present a framework for harmonising such plasma lipidomic datasets with different levels of granularity in their lipid measurements. Our method utilises elastic-net prediction models, constructed from high-resolution lipidomics reference datasets, to predict unmeasured lipid species in lower-resolution studies. The approach involves (1) constructing composite lipid measures in the reference dataset that map to less resolved lipids in the target dataset, (2) addressing discrepancies between aligned lipid species, (3) generating prediction models, (4) assessing their transferability into the targe dataset, and (5) evaluating their prediction accuracy. To demonstrate our approach, we used the AusDiab population-based cohort (747 lipid species) as the reference to impute unmeasured lipid species into the LIPID study (342 lipid species). Furthermore, we compared measured and imputed lipids in terms of parameter estimation and predictive performance, and validated imputations in an independent study. Our method for harmonising plasma lipidomic datasets will facilitate model validation and data integration efforts.


Subject(s)
Lipidomics , Plasma , Humans , Mass Spectrometry , Lipids
13.
Diabetes Obes Metab ; 26(5): 1731-1745, 2024 May.
Article in English | MEDLINE | ID: mdl-38351663

ABSTRACT

AIM: Acyl-coenzyme A dehydrogenase family member 10 (ACAD10) is a mitochondrial protein purported to be involved in the fatty acid oxidation pathway. Metformin is the most prescribed therapy for type 2 diabetes; however, its precise mechanisms of action(s) are still being uncovered. Upregulation of ACAD10 is a requirement for metformin's ability to inhibit growth in cancer cells and extend lifespan in Caenorhabditis elegans. However, it is unknown whether ACAD10 plays a role in metformin's metabolic actions. MATERIALS AND METHODS: We assessed the role for ACAD10 on whole-body metabolism and metformin action by generating ACAD10KO mice on a C57BL/6J background via CRISPR-Cas9 technology. In-depth metabolic phenotyping was conducted in both sexes on a normal chow and high fat-high sucrose diet. RESULTS: Compared with wildtype mice, we detected no difference in body composition, energy expenditure or glucose tolerance in male or female ACAD10KO mice, on a chow diet or high-fat, high-sucrose diet (p ≥ .05). Hepatic mitochondrial function and insulin signalling was not different between genotypes under basal or insulin-stimulated conditions (p ≥ .05). Glucose excursions following acute administration of metformin before a glucose tolerance test were not different between genotypes nor was body composition or energy expenditure altered after 4 weeks of daily metformin treatment (p ≥ .05). Despite the lack of a metabolic phenotype, liver lipidomic analysis suggests ACAD10 depletion influences the abundance of specific ceramide species containing very long chain fatty acids, while metformin treatment altered clusters of cholesterol ester, plasmalogen, phosphatidylcholine and ceramide species. CONCLUSIONS: Loss of ACAD10 does not alter whole-body metabolism or impact the acute or chronic metabolic actions of metformin in this model.


Subject(s)
Diabetes Mellitus, Type 2 , Metformin , Male , Female , Mice , Animals , Diabetes Mellitus, Type 2/metabolism , Mice, Inbred C57BL , Metformin/pharmacology , Glucose/metabolism , Insulin , Ceramides , Sucrose , Diet, High-Fat/adverse effects
14.
EBioMedicine ; 100: 104949, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38199043

ABSTRACT

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are neurodevelopmental conditions with early life origins. Alterations in blood lipids have been linked to ADHD and ASD; however, prospective early life data are limited. This study examined (i) associations between the cord blood lipidome and ADHD/ASD symptoms at 2 years of age, (ii) associations between prenatal and perinatal predictors of ADHD/ASD symptoms and cord blood lipidome, and (iii) mediation by the cord blood lipidome. METHODS: From the Barwon Infant Study cohort (1074 mother-child pairs, 52.3% male children), child circulating lipid levels at birth were analysed using ultra-high-performance liquid chromatography-tandem mass spectrometry. These were clustered into lipid network modules via Weighted Gene Correlation Network Analysis. Associations between lipid modules and ADHD/ASD symptoms at 2 years, assessed with the Child Behavior Checklist, were explored via linear regression analyses. Mediation analysis identified indirect effects of prenatal and perinatal risk factors on ADHD/ASD symptoms through lipid modules. FINDINGS: The acylcarnitine lipid module is associated with both ADHD and ASD symptoms at 2 years of age. Risk factors of these outcomes such as low income, Apgar score, and maternal inflammation were partly mediated by higher birth acylcarnitine levels. Other cord blood lipid profiles were also associated with ADHD and ASD symptoms. INTERPRETATION: This study highlights that elevated cord blood birth acylcarnitine levels, either directly or as a possible marker of disrupted cell energy metabolism, are on the causal pathway of prenatal and perinatal risk factors for ADHD and ASD symptoms in early life. FUNDING: The foundational work and infrastructure for the BIS was sponsored by the Murdoch Children's Research Institute, Deakin University, and Barwon Health. Subsequent funding was secured from the Minderoo Foundation, the European Union's Horizon 2020 research and innovation programme (ENDpoiNTs: No 825759), National Health and Medical Research Council of Australia (NHMRC) and Agency for Science, Technology and Research Singapore [APP1149047], The William and Vera Ellen Houston Memorial Trust Fund (via HOMER Hack), The Shepherd Foundation, The Jack Brockhoff Foundation, the Scobie & Claire McKinnon Trust, the Shane O'Brien Memorial Asthma Foundation, the Our Women Our Children's Fund Raising Committee Barwon Health, the Rotary Club of Geelong, the Ilhan Food Allergy Foundation, Geelong Medical and Hospital Benefits Association, Vanguard Investments Australia Ltd, the Percy Baxter Charitable Trust, and Perpetual Trustees.


Subject(s)
Attention Deficit Disorder with Hyperactivity , Autism Spectrum Disorder , Carnitine/analogs & derivatives , Infant , Infant, Newborn , Humans , Male , Female , Autism Spectrum Disorder/epidemiology , Autism Spectrum Disorder/etiology , Cohort Studies , Attention Deficit Disorder with Hyperactivity/epidemiology , Attention Deficit Disorder with Hyperactivity/etiology , Fetal Blood , Prospective Studies , Lipids
15.
J Lipid Res ; 65(2): 100494, 2024 02.
Article in English | MEDLINE | ID: mdl-38160756

ABSTRACT

HDL particles vary in lipidome and proteome, which dictate their individual physicochemical properties, metabolism, and biological activities. HDL dysmetabolism in nondiabetic hypertriglyceridemia (HTG) involves subnormal HDL-cholesterol and apoAI levels. Metabolic anomalies may impact the qualitative features of both the HDL lipidome and proteome. Whether particle content of bioactive lipids and proteins may differentiate HDL subclasses (HDL2b, 2a, 3a, 3b, and 3c) in HTG is unknown. Moreover, little is known of the effect of statin treatment on the proteolipidome of hypertriglyceridemic HDL and its subclasses. Nondiabetic, obese, HTG males (n = 12) received pitavastatin calcium (4 mg/day) for 180 days in a single-phase, unblinded study. ApoB-containing lipoproteins were normalized poststatin. Individual proteolipidomes of density-defined HDL subclasses were characterized prestatin and poststatin. At baseline, dense HDL3c was distinguished by marked protein diversity and peak abundance of surface lysophospholipids, amphipathic diacylglycerol and dihydroceramide, and core cholesteryl ester and triacylglycerol, (normalized to mol phosphatidylcholine), whereas light HDL2b showed peak abundance of free cholesterol, sphingomyelin, glycosphingolipids (monohexosylceramide, dihexosylceramide, trihexosylceramide, and anionic GM3), thereby arguing for differential lipid transport and metabolism between subclasses. Poststatin, bioactive lysophospholipid (lysophosphatidylcholine, lysoalkylphosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidylinositol) cargo was preferentially depleted in HDL3c. By contrast, baseline lipidomic profiles of ceramide, dihydroceramide and related glycosphingolipids, and GM3/phosphatidylcholine were maintained across particle subclasses. All subclasses were depleted in triacylglycerol and diacylglycerol/phosphatidylcholine. The abundance of apolipoproteins CI, CII, CIV, and M diminished in the HDL proteome. Statin treatment principally impacts metabolic remodeling of the abnormal lipidome of HDL particle subclasses in nondiabetic HTG, with lesser effects on the proteome.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hyperlipidemias , Hypertriglyceridemia , Quinolines , Male , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Proteome , Diglycerides , Lipidomics , Ceramides , Cholesterol/metabolism , Hypertriglyceridemia/drug therapy , Cholesterol, HDL , Triglycerides , Phosphatidylcholines
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